Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA.

Abstract

The most intractable feature of drug addiction is the high rate of relapse, even following extended periods of abstinence from drug-taking. Evidence suggests that allowing rats extended access to cocaine self-administration leads to behavioral characteristics in these animals that are consistent with the development of addiction in humans. In the current study, rats were allowed to self-administer cocaine over a total of 22 daily sessions, the final seven of which were long-access (LgA) sessions of 6 h duration. Assessments of reinstatement of drug-seeking behavior were made following reintroduction to the drug-taking environment and noncontingent priming with either conditioned stimulus (CS) or cocaine in both extinguished and abstinent subject groups. Three separate groups of rats were treated with either saline or D-serine (100 mg/kg i.p.) administered 2 h prior to, or immediately following, each extinction training session. Saline-treated LgA rats were resistant to the effects of extinction training to reduce noncontingent priming of reinstatement of drug-seeking behavior with either CS or cocaine. In contrast, treatment with D-serine either before or immediately following the sessions resulted in a significant enhancement in the ability of extinction training to reduce cocaine-primed reinstatement of drug-seeking behavior. These results suggest that D-serine can act to enhance the consolidation of extinction learning in LgA rats, and is therefore a promising adjunctive agent along with behavioral therapy for the treatment of cocaine addiction.

Cocaine self-administration and escalation of drug intake. (A) Cocaine self-administration training was carried out over three phases: 1st starting from day1 with an FR-1 schedule during short-access (ShA, 90 min) daily sessions, 2nd starting from day 11 with an Fr-3 schedule, 3rd starting from day 16 with long-access (LgA, 360 min) daily sessions. The results are the mean ± SEM (n=33) of daily infusions. (B) Three day average earned infusions during the first 60 min for each of these phases are illustrated from the days indicated by the horizontal bars in panel A (ShA/FR-1, ShA/FR-3, LgA/FR-3) and show a significant increase in earned infusions during the LgA phase compared with either ShA group (†, p<0.05, one-way ANOVA/Holm-Sidak).

Incubation and extinction responding. Data are the mean ± SEM of active lever presses (left bar of pair) during the first 10 min of the extinction session for the indicated groups. The right bar of each pair is the inactive lever responding. (A) Active lever responding six days after cocaine self-administration (A6 group, n= 8) was significantly increased compared to one day (A1 group, n= 8) after cocaine self-administration (†, p<0.05, one-way ANOVA/Holm-Sidak). (B) Active lever responding for the indicated saline, D-serine pre, and D-serine post extinguished groups (n= 8,9,8, respectively) did not differ significantly. Active lever responding in the A6 group in panel A. was significantly increased compared with each of the extinguished groups in panel B. (##, p<.01, one-way ANOVA/Holm-Sidak).

Cocaine primed reinstatement of drug-seeking behavior. (A-C) Data are the mean ± SEM of active lever presses for the indicated treatment groups (n= 8,9,8,8, respectively) during 30 min periods before (left bar) and after (right bar) noncontingent i.v. drug priming at the indicated doses. (A) Following a single 0.25mg/kg infusion, active lever responding did not differ significantly among all groups. (B) Following a single 0.5mg/kg infusion, active lever responding was significantly increased in both the saline extinguished and saline abstinent groups (**, p<0.01; *, p<0.05; two-way ANOVA/Holm-Sidak), and responding of the D-serine treatment groups was significantly decreased as compared with the saline abstinent group (††, p<0.01; †, p<0.05; two-way ANOVA/Holm-Sidak). Also, the D-serine pretreatment group was significantly decreased as compared with the saline extinction group (#, p<0.05; two-way ANOVA/Holm-Sidak). (C) Following a single 1mg/kg infusion, active lever responding was significantly increased in both the saline extinguished and saline abstinent groups (**, p<0.01; two-way ANOVA/Holm-Sidak), and responding of the D-serine treatment groups was significantly decreased as compared with either the saline abstinent group (††, p<0.01; two-way ANOVA/Holm-Sidak) or the saline extinction group (#, p<0.05; two-way ANOVA/Holm-Sidak). (D) Summary dose-response of the active lever presses for the indicated treatment groups and drug priming doses. Note that 0.5mg/kg was used during cocaine self-administration.